Plasmapheresis in obstetrics and neonatology


Preeclampsia is a serious complication of pregnancy, one of the leading causes of maternal and perinatal morbidity and mortality. In most cases it is secondary or combined nature, developing on the background of other types of extragenital pathology – diseases of the kidney (pyelonephritis, glomerulonephritis), obesity, hypertension, diabetes.

Old version of this complication – toxemia of pregnancy – more fully reflect the essence of this pathology. However, among the many hypotheses about the etiology and pathogenesis of preeclampsia is prevalent view of the leading role of generalized spasm of peripheral vessels with impaired microcirculation. And supposedly due to spasm of the arterioles increases vascular permeability and transition fluid in tissues and hypovolemia.

Of course, we must accept the presence of such processes, but they are developing, in all probability, in reverse order, that is, really is a violation of vascular permeability, but not as a result of spasm of blood vessels, and due to the accumulation in the blood of some toxic membranotropic substances. But at the same time developing a toxic edema interstitial with transition there also proteins, primarily albumin, and certainly accompanied by hypoproteinemia. The latter, as a result of reducing the colloid osmotic pressure of blood plasma, which inevitably leads to a decrease in circulating blood volume, and an adaptive response as when it occurs arteriolar spasms to reduce the volume of the vascular bed and the blood pressure necessary to maintain.

Therefore, we must first of all interested in those changes in the body that determine the development of endogenous intoxication syndrome. There are reports of significant violations of biochemical homeostasis in preeclampsia, in particular - disorders of the kallikrein-kinin system, lipid peroxidation, proteolysis with the accumulation of a number of toxic metabolites and BAS - kinins, histamine, serotonin, malondialdehyde, diene conjugates, medium weight oligopeptides. Thus, according to V.V. Vetrov (1990, 2000), the levels of “middle molecules” in normal pregnant and preeclampsia I, II and III degrees up 247.0 ± 7.2, 282.8 ± 8.4; 363.2 ± 6.7 end 534.2 ± 13.5 units respectively, and in some cases (eclampsia anuric) reach 1000 units.

May play a role, and endotoxin (bacterial lipopolysaccharide) are released into the bloodstream when "irritable bowel syndrome" for violations of its motor-evacuation function and flatulence. In such cases, 86% of pregnant women registered threatened miscarriage [Demina TN, Suhurova LS, 2008].

These products also are capable of increasing the permeability of the vascular endothelium with access to the interstitium not only fluid, but also protein, thereby causing hypovolemia and generalized vasospasm respectively.

In women with the metabolic syndrome, obesity and gestational diabetes preeclampsia develops much more and is accompanied by asphyxia and neonatal cerebral blood flow disorders  [Nikolaeva-Ball D.R. et al, 2008].

Not ruled out an autoimmune component of preeclampsia when autoantibodies activate angiotensin receptors that confirm special studies in animal experiments [Xia Y., Kellems R.E., 2009]

Preeclampsia is accompanied by a systemic inflammatory response syndrome with the release of cytokines IL-6 and TNF-α and disorder of lipid peroxidation with depletion of the antioxidant defense capacity. Toxic damage of hepatocytes promotes additional release of C-reactive protein [Medvinsky I.D. et al, 2000].

The role of a vascular endothelial growth factor (VEGF), placental growth factorf (PIGF) and soluble fms-like tyrosine-kinase receptor-1 which detection is possible even before emergence of clinical signs of a preeclampsia is revealed [Andraweera P.H Proslezhitvatsya. et al., 2012] which removal from maternal circulation can help to prevent development of a preeclampsia [Alasztics B. et al., 2014].

The result is interstitial edema and hypoxia organs and tissues with secondary deterioration of their functions. In severe cases of eclampsia occurs on a background of multiple organ failure – loss of consciousness, seizures (brain edema), severe parenchymal respiratory failure (toxic pulmonary edema – respiratory distress syndrome [RDS]), anuria, liver failure, hypertension with impaired microcirculation, and often with retinal detachment.

Development of multiple organ disorders contributes to a series of vicious circles, among which the leading role belongs nephropathy, when due to the toxic effects begin to suffer the main elements of the nephron – glomerular filtration and tubular reabsorption. This process results in a progressive increase in the concentration of toxic substances of middle weight that normal kidney safely brought to the urine. And it takes away some researchers nephropathy leading role in exacerbating the disorders of homeostasis and progression of preeclampsia [Vetrov V.V., 2000].

Membranotropic biologically active substances (BAS) affect not only the vascular endothelium, but also in other cell membrane structures, disrupting transmembrane exchange of electrolytes and other substances. No exception, and the cells of the blood itself, taking the first blow of toxic compounds. In particular, the membranotropic products stimulate platelet aggregation, thereby contributing, development of disseminating intravascular coagulation (DIC), platelet aggregation and thrombocytopenia, increased concentration of fibrin degradation products, soluble fibrin monomer complexes and reduced fibrinolysin activity [Chaika V.K. et al, 2004]. And it develops consumption of coagulopathy, which is the cause of severe bleeding during delivery. 

In preeclampsia can be traced and immune mechanisms of conflict between mother and fetus also. There is revealed part of fetal antibodies and autoantibodies in the pathogenesis of preeclampsia. Can not exclude the role of local immunity to immune damage the placenta and increase the activity of natural killer cells, deposition of the circulating immune complexes (CIC) in the vessels of the placenta and kidney, kinins activation, increased levels of thromboxane, fibrin deposition. This leads to ischemia of the placenta and kidney development of hypertension. Antibodies and CIC seating on platelets, activate their adhesiveness to the release of ADP and serotonin, which triggers a cascade of DIC.

Special electrophysiological studies show that at the earliest clinical manifestations of preeclampsia there can already detect signs of placental circulation disturbances and intrauterine hypoxia. This is understandable, since all middle weight toxic products freely cross the placental barrier, which was confirmed by our own research – the level of middle molecules in the blood of pregnant women with symptoms of preeclampsia are completely consistent with their concentration in placental blood, i.e., in the fetal blood.

This shows that all membranotoxic products that cause deteriorations of endothelial permeability, edema, and toxic disorders of the organs of pregnant, just break and placental circulation also, with degenerative processes in the placenta with sclerosis, necrosis, hemorrhage and its partial detachment that is driving force for premature labor and severe bleeding. Thus both the maternal and cord blood and even in the amniotic fluid increases the content of IL-8 and TNF-a. Violations of placental circulation also determine gas exchange disorders and fetal hypoxia, delay its development the fetus retardation [Radzinsky V.E. et al., 1999].

It endotoxemia, causing impaired permeability of the vascular wall and leads to the development of interstitial edema is actually toxic, promotes fluid retention pregnant. The appearance of protein in the urine also suggests increasing the toxic permeability of renal vessels. Nevertheless, O.V.Grischenko et al.. (2008) is the increase in extracellular fluid volume during pregnancy, reaching 4,4-5 liters and accompanied by edema of the lower extremities, deem appropriate physiological pregnancy. However, it is difficult to imagine that such fluid accumulation volume is a normal condition.

Prolonged fetal conditions such toxemia breaks all processes of development of fetal organs and systems, up to his death in utero. The intrauterine fetal growth retardation syndrome is one of the leading places in the structure of perinatal morbidity and mortality. Its frequency varies from 3 to 24% of mature and from 18 to 24% of premature babies. In children with intrauterine fetal growth retardation and perinatal mortality and morbidity is 2-3 times higher than those in children with normal body weight and reaches 80-100% [Likhacheva N.V., 2000].

There is the most actual problem of neurological disorders in preterm. In particular, the incidence of severe neurological disorders they can reach 44-47% [Savelieva G.M. et al., 1999; Crane J.M. et al., 2015]. Thus, among neonates with birth weight below 1000g most of die in the first hours and days of life, and in survivors severe disabling CNS disorders reach 28%, and less rough - 44%. Of the 100 such children born healthy are only 8-15% [Kulakov V.I. et al, 1998].

These children in the future will suffer encephalopathy with mental retardation, pneumopathies with respiratory distress syndrome, hepato-nephropathy with the formation of chronic hepatitis and even early cirrhosis, chronic pyelonephritis, will lag behind in physical development. The incidence of lung disease in children whose mothers suffered preeclampsia during pregnancy is twice that of the children born in normal pregnancy [Mahon B.E. et al., 2007]. Allergic dermatitis (atopic eczema) in such cases also occur 3-4 times more likely [Evsyukova I.I., 2001]. Increases the risk of perinatal and neonatal sensitization, reaching 31.8%, and at increased load pregnant drugs it comes to 66.6% [Gavalov SM, 2001].

V.K.ChaykaandT.N.Demina(2003)rightly point out thatas a bookmarkmain organs and systems, and, ultimately, human health is largely dependenton the conditions offetal developmentandthe factorsof the environment,which inaffectit.   Afetalexternal environmentis the internalenvironment of the bodyof his mother.

Pregnancy - is a physiological state of immunodeficiency, which allows to block the struggle against foreign antigens of the fetus to the mother, who is actually a "transplant". However, disturbances of biochemical homeostasis in preeclampsia cause additional secondary immunodeficiency toxic origin. The same processes occur in the fetus, the immune system is still evolving, but under prolonged exposure to toxic products of the immune system development even more inhibited and the child is born in such cases as completely defenseless before microorganisms (there are increased the frequency of septic complications, respiratory viral diseases) and the xenobiotics (frequent allergies – diathesis, asthmatic bronchitis), and before the tumor cells (rejuvenation of cancer). Virtually it holds the acquired immunodeficiency syndrome, like AIDS actually, with all its fatal consequences.   

Preeclampsia or toxemia of pregnancy – it can be said the only disease in the name includes the term "toxicosis", but a statement of this fact is far means that detoxification is the main therapeutic measure. Instead measures targeted removal of pathological products from the body of a pregnant, she is assigned a number of different drugs, often far from indifferent to the fetus. Many of them, each in their own way, seem to be quite justified – euphyllin, komplamin, nikoshpan, curantyl, trental,  heparin, glucose,  potassium orotate, glutamic acid, methionine, tocopherol, essentiale, vitamins and many other [Bychkov V.I. et al., 1999; Strizhakov A.N. et al., 2000].

On the other hand, it is obvious that instead of introducing any additional substances should, on the contrary, remove pathological products and best this can be accomplished only by means of the apheresis therapy.

One of the first V.V.Vetrov with detoxification in preeclampsia has used hemosorption. However, despite the positive results obtained by cupping manifestations of preeclampsia, prolongation of pregnancy and the birth of healthy babies and live (Vetrov V.V., Levanovich V.V., 1990), this method at the time did not get due recognition and distribution in obstetric practice.

Understanding the rationale for such a cautious stance obstetricians on the one hand and the need for detoxification therapy in preeclampsia, on the other hand, we decided to use at first the safest and non-invasive method of detoxification – enterosorption using polyphepane. Given that observed during pregnancy disorder known enzymatic and motor functions of the intestine with impaired processes of digestion, dysbiosis, which leads to the appearance of enterogenous toxins (endotoxin) that getting into the bloodstream exacerbate toxicosis, this alone is an indication for enterosorption.

However, at the level of the intestinal villi is a constant process of fluid flow from the vascular bed (5-10 liters per day) consisting of all components of plasma except proteins. As a major toxic metabolites in preeclampsia are of middlemolecular weight, then they have the ability to temporarily leave the bloodstream and enter the intestinal lumen. If they are there to meet with the activated surface enterosorbent, thanks to its electrochemical properties (most of their molecules contain free radicals) are adsorbed on them and never returned to the circulation during the reverse fluid reabsorption in the intestine [Enterosorption, 1991] .

Method in the treatment of pre-eclampsia enterosorption was used by us in the course of medical and environmental research in the Voljsky sity (near Volgograd) were identified both a higher perinatal mortality on the background of complicated pregnancy and a greater children incidences. Indications for enterosorption served as early toxicosis and manifestations of late toxicosis at all stages of pregnancy. Treatment was performed as an outpatient under the supervision of physicians antenatal clinics, and in the Department of Pathology of pregnancy hospital. The course consisted of receiving polyphepane 1 tablespoon three times a day on an empty stomach for 7-10 days. If necessary, these courses were repeated at intervals of not less than 1 month, up to the period immediately preceding the delivery.

Effectiveness of such apheresis therapy was most prominently in the early toxicosis when vomiting stopped 2-3 days after starting treatment. When late toxicosis (preeclampsia) also noted smoothing their manifestations – normalized blood pressure, reduce edemas, disappeared or decreased levels of protein in the urine, decreased degree of intrauterine fetal hypoxia, starred threat of premature birth. Any complications and side effects associated with enterosorption not mentioned [Voinov V.A. et al., 1994].

There is leaded a more detailed analysis of 780 stories of childbirth and newborn status with the release of the two groups. 1st group consisted of 183 children whose mothers took during pregnancy polyphepane, 2nd – 597 children whose mothers did not take it.

This analysis showed that the perinatal mortality rate as a whole was 10,2‰ (8 from 780), but in the 1st group of children whose mothers took Polyphepanum, died only one newborn (of twins) weighing 1110 g, which was 5.4‰, against 11,7‰  (p<0,01) in the 2nd group of children whose mothers did not take polyphepane. It should be borne in mind that in this city over the previous years levels of perinatal mortality were 16.2‰ and 19.4‰, and among the residents of the Voljsky, who gave birth in the regional hospital, where the enterosorption method was not implemented (as in the guide a women's clinic in the city), perinatal mortality rate for the corresponding period in 1993 amounted to 21.7‰ (10 neonates from 460).

There was identified anda clear tendencytoreduce the frequencyof pulmonary complications (from whichmainlydependsearly neonatal mortality)in the group ofchildren whose motherstookduring pregnancypolyphepane. In addition, thereobservedlower incidence ofneurological complications inthissubgroup ofinfants.

Indirect indicator of the health of newborns is the possibility of discharge home with his mother, or, otherwise, the need to relocation for further treatment in the department of pathology of the newborn, or even more intensive therapy in the intensive care baby unit. Analysis of these cases showed that the need for relocation of newborns whose mothers took polyphepane as a children's hospital and in the ICU, there is even less likely than in the control group (1.1 and 3.3%, respectively), while it is in this subgroup of children such a need would have to occur much more often due to complications of pregnancy in their mothers. This, albeit indirectly indicates a higher level of health of newborns whose mothers took preventive detoxification courses in various forms of toxicosis pregnant and comorbidity. This confirms the fact that among the 16 children analyzed group died from various causes during the first year of life, there was not a single child whose mothers took polyphepane.

Thus, thesedata show thatin the absence ofanynegative sideeffects, even amildpreventivedetoxificationusingpolyphepanelargelyprevents the development ofa number of seriouscomplicationsin newborns.However, we areaware ofandthatis not in allcases,such therapyis sufficientin relievingsevere manifestationsof preeclampsia. Laterwe used andamuch more efficient methodof apheresist therapyasplasmapheresis.

In the D.O. Ott Institute of Obstetrics and Gynecology name (St. Petersburg) in early preeclampsia, characterized by repeated vomiting with weight loss and acetonuria courses membrane plasmapheresis led to a significant improvement in the general condition. Stopped nausea and vomiting, appetite appeared, restored body weight, decreased by 77% the level of middle weight molecules. All women managed to carry a pregnancy. Additional justification for such an active approach to therapy of early toxicity are evidence that in violation of the uteroplacental circulation in the I trimester up to 88.5 % of pregnant women subsequently develop preeclampsia [O.B. Panina, 2000; Chortatos A. et al., 2015].

In the Snegirev maternity hospital (St. Petersburg) in 123 pregnant women with preeclampsia was also used membrane plasmapheresis. 3-5 sessions performed with the removal of up to 30% circulating plasma volume (CPV) at intervals of 2-3 days. The compensation is carried isovolemic mode only crystalloid solutions. After plasmapheresis pregnant noted improvement in health, stoped headaches, decreased edema, increased urine output, decreased by 20% the level of hypertension. Normalized transaminase (ALT) and bilirubin levels, decreased plasma coagulation factors, although remained elevated adhesive-platelet aggregation properties, but in any case not observed bleeding during delivery. Stable clinical effect was observed in 39 pregnant women with preeclampsia mild. All of them gave birth in time and sent home with the children. In a group of 84 pregnant women with severe preeclampsia clinical effect was less resistant – 60% of women were discharged home ahead of schedule and 40% of newborn body weight at birth was until 1500, however, perinatal loss had no children. All of them recovered and were discharged after treatment and rehabilitation in children's hospitals in the city.

When comparing comparable groups of women with pre-eclampsia has been shown that the use of apheresis therapy has reduced the incidence of intrauterine infections, prematurity, hypoxia and fetal malnutrition in 2.6, 1.6, 1.5 and 1.3 times respectively. In this case, the control group (49 women) died perinatally 2 fetal from intrauterine infection and hypoxia, whereas in the study group (46 women), perinatal mortality was not [Vetrov V.V., 2000]. At severe depression of liver function apheresis therapy started with hemosorption and followed by membrane plasmapheresis. Over 10 years have been on the treatment of 1049 pregnant women with preeclampsia in the absence of perinatal mortality in this group [Vetrov V.V. et al., 2009; Serov V.N. et al., 2011].

Using plasmapheresis it helps normalize blood clotting, preventing bleeding and reduce the risk of thromboembolic complications [Chaika V.K. et al., 2004]. And there was the normalization of the main markers of intoxication – medium weight oligopeptides and leukocyte index of intoxication [Chermnykh S.V., 2006]. Even in preterm labor outcomes of gestation in women treated for pregnancy by apheresis therapy were the best. If the control group 70% of the infants required relocation to the intensive care unit at Children's Hospital, the main group of such a need arose in 2 times less [Vetrov V.V. et al., 2003]. Best results are obtained when plasmapheresis was combined with ozone therapy [Chermnykh S.V. et al., 2006].

A great experience with plasmapheresis in obstetrics and in the treatment of preeclampsia, in particular, gained in the Scientific Center for Obstetrics, Gynecology and Perinatology, Moscow [Kulakov V.I., 1998; Serov V.N., Fedorova T.A., 2003, Serov V.N. et al., 2011]. As a result of plasmapheresis noted distinct decrease in proteinuria and improvement of renal function with an increase in glomerular filtration rate, diuresis and clearance minute indicators. There were improved performance both fetoplacental circulation and fetal status according to CTG, normalized system of lipid peroxidation with decreased blood concentrations of toxic products of lipid peroxidation. It was noted faster regression of edema syndrome, reducing the frequency of septic complications from 70% to 16%, lactation persisted in 53% (vs. 30% for conventional therapy), 2.7 times decreased maternal mortality, decreased puerperal stay in the maternity hospital in 1.5 times [Pyregov A.V., 2005].

In Ukraine, the largest (20-year) experience of apheresis therapy in obstetric practice accumulated in the Donetsk regional center of maternity and childhood [Chaika V.K. et al., 2009]. Timely inclusion membrane plasmapheresis in complex intensive treatment of severe preeclampsia allowed to reduce manifestations of endogenous intoxication prolong pregnancy up to 48 hours, followed by delivery to prevent maternal mortality and multiple organ dysfunction stabilized level on stage, did not require replacement therapy [Demina T.N. et al., 2009].

The plasma exchange finds application and in Germany as "rescue therapy" at refractory forms of a preeclampsia [Müller-Deile J., Schiffer M., 2014].

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